Mechanisms that differentiate dendrite development from axon development

区分树突发育和轴突发育的机制

• 批准号: 9446382
• 负责人: BING YE
• 金额: $ 38.12万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9446382
• 关键词: 3' Untranslated Regions; Alpha Cell; Axon; Axonal Transport; Binding Proteins; Biochemical Genetics; Biological; Cell Adhesion Molecules; Cell Nucleus; Cell Size; Cells; Defect; Dendrites; Development; Down Syndrome Cell Adhesion Molecule; Drosophila genus; Dynein ATPase; Goals; Growth; Heterogeneous-Nuclear Ribonucleoproteins; Knowledge; Label; Larva; Lead; Leucine Zippers; Location; Mediating; Mental disorders; Mission; Modeling; Molecular; Molecular Genetics; Morphology; Natural regeneration; Nerve Degeneration; Nerve Regeneration; Neurodevelopmental Disorder; Neurons; Neurosciences; Pathogenesis; Pathway interactions; Phosphorylation; Phosphotransferases; Play; Poly(A)-Binding Proteins; Presynaptic Terminals; Process; Proteins; Proteomics; Public Health; RNA interference screen; RNA-Binding Proteins; Regulation; Research; Role; Signal Transduction; Specificity; System; Techniques; Testing; Translational Regulation; Translations; United States National Institutes of Health; Work; axon growth; base; design; genetic approach; human disease; improved; in vivo; injured; innovation; insight; nervous system disorder; neural circuit; neuron development; newborn neuron; novel; retrograde transport; transcription factor

How a neuron’s dendrites and axons develop into distinct morphology—which is fundamental to the assembly of neural circuits—is poorly understood. Understanding the mechanisms that differentiate dendrite and axon development, therefore, is a vital goal in developmental neuroscience. Several regulatory mechanisms that are dedicated to either dendrite-specific or axon-specific growth in vivo have been identified by taking advantage of a Drosophila system. In addition, a molecular pathway that suppresses dendritic growth but promotes axonal growth within the same neuron (i.e., a bimodal mechanism) has been located upstream of these dedicated mechanisms. The bimodal regulation provides a unique mechanism for generating morphological diversity in neurons, and is relevant for the design of effective strategies to regenerate an injured or diseased nervous system. The long-term goal of this research is to define how a neuron develops into distinct subcellular parts and how defects in this process lead to human disease. The objective of the proposed studies is to uncover the molecular and cellular mechanisms of bimodal controls of dendritic and axonal growth. Recent studies have shown that the evolutionarily conserved dual leucine zipper kinase/Wallenda (DLK/Wnd) pathway is a bimodal regulator of dendritic and axonal growth, and that this pathway regulates the expression levels of a transcription factor (Knot) and a cell adhesion molecule (Dscam) to control dendritic and axonal growth, respectively. Preliminary studies suggest a novel concept: Translational regulation through RNA-binding proteins is at the core of bimodal control of dendritic and axonal growth. The following model, which integrates specific molecules and regulations with their spatial locations for bimodal control, will be tested: The DLK/Wnd pathway regulates two distinct RNA-binding proteins to control PABP-dependent initiation of Dscam translation in axon terminals for axonal growth and Knot expression in the cell body for dendritic growth, respectively. This model will be tested by identifying (a) the molecular mechanism by which the DLK/Wnd pathway regulates axon-terminal development and dendritic branch development and (b) the subcellular locations at which the DLK/Wnd pathway regulates downstream factors to instruct the differential growth of dendrites and axons. The proposed research is innovative because it proposes a novel concept in the differential development of dendrites and axons and employs several innovative techniques that are well suited for this line of research. This research is significant because it is expected to offer key insights into the coordination between dendritic and axonal development, identify a critical role translational control plays in the differential development of dendrites and axons, discover novel mechanisms by which the DLK/Wnd pathway functions in neurons, and provide insights into the pathogenesis of neurodevelopmental disorders.

神经元的树突和轴突如何发育成独特的形态-这是组装的基础 对神经回路的理解还很有限。了解树突和轴突的分化机制 因此，发育是发育神经科学的一个重要目标。一些监管机制， 致力于树突特异性或轴突特异性体内生长已经通过利用 一个果蝇系统。此外，抑制树突生长但促进轴突生长的分子途径 同一神经元内的生长（即，双峰机制）已经位于这些专用的 机制等双峰调节提供了一个独特的机制，产生形态多样性， 神经元，并且与设计有效的策略以再生受损或患病的神经元相关 系统这项研究的长期目标是确定神经元如何发育成不同的亚细胞部分 以及这个过程中的缺陷如何导致人类疾病。拟议研究的目的是揭示 树突和轴突生长的双峰控制的分子和细胞机制。最近的研究 表明进化上保守的双亮氨酸拉链激酶/瓦伦达（DLK/Wnd）途径是一个双峰 树突和轴突生长的调节因子，并且该途径调节转录因子的表达水平。 细胞因子（Knot）和细胞粘附分子（Dscam）分别控制树突和轴突生长。 初步的研究提出了一个新的概念：通过RNA结合蛋白的翻译调控是在转录水平。 双峰控制树突和轴突生长的核心。下面的模型，它整合了特定的分子 和调控与其空间位置的双峰控制，将进行测试：DLK/Wnd途径调节 两种不同的RNA结合蛋白控制轴突终末中Dscam翻译的PABP依赖性起始 分别用于轴突生长和用于树突生长的细胞体中的Knot表达。这一模式将 通过鉴定（a）DLK/Wnd途径调节轴突末端的分子机制来测试 和（B）DLK/Wnd的亚细胞位置 信号通路调节下游因子以指导树突和轴突的差异生长。拟议 研究是创新的，因为它提出了一个新的概念，在不同的发展树突， 轴突，并采用了几种创新的技术，非常适合这一研究路线。本研究是 意义重大，因为它有望为树突和轴突之间的协调提供关键见解 发展，确定一个关键的作用，翻译控制发挥的差异发展的树突和 轴突，发现DLK/Wnd通路在神经元中发挥作用的新机制，并提供见解 神经发育障碍的发病机制